{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T05:49:30Z","timestamp":1779169770657,"version":"3.51.4"},"reference-count":72,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T00:00:00Z","timestamp":1744070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01 CA074397"],"award-info":[{"award-number":["R01 CA074397"]}]},{"name":"National Institutes of Health","award":["R01 CA074397-S1"],"award-info":[{"award-number":["R01 CA074397-S1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Human papillomavirus type 16 (HPV16) is an etiological agent of human cancers that requires endocytosis to initiate infection. HPV16 entry into epithelial cells occurs through a non-canonical endocytic pathway that is actin-driven, but it is not well understood how HPV16\u2013cell surface interactions trigger actin reorganization in a way that facilitates entry. This study provides evidence that Wiskott\u2013Aldrich syndrome protein family verprolin-homologous proteins 1 and 2 (WAVE1 and WAVE2) are molecular mediators of actin protrusions that occur at the cellular surface upon HPV addition to cells, and that this stimulation is a key step prior to endocytosis and intracellular trafficking. We demonstrate through post-transcriptional gene silencing and genome editing that WAVE1 and WAVE2 are critical for efficient HPV16 infection, and that restoration of each in knockout cells rescues HPV16 infection. Cells lacking WAVE1, WAVE2, or both internalize HPV16 at a significantly reduced rate. Microscopic analysis of fluorescently labeled cells revealed that HPV16, WAVE1, WAVE2, and actin are all colocalized at the cellular dorsal surface within a timeframe that precedes endocytosis. Within that same timeframe, we also found that HPV16-treated cells express cellular dorsal surface filopodia, which does not occur in cells lacking WAVE1 and WAVE2. Taken together, this study provides evidence that WAVE1 and WAVE2 mediate a key step prior to HPV entry into cells that involves actin reorganization in the form of cellular dorsal surface protrusions.<\/jats:p>","DOI":"10.3390\/v17040542","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T07:49:02Z","timestamp":1744184942000},"page":"542","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Human Papillomavirus Type 16 Stimulates WAVE1- and WAVE2-Dependent Actin Protrusions for Endocytic Entry"],"prefix":"10.3390","volume":"17","author":[{"given":"Daniel J.","family":"Fernandez","sequence":"first","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA"},{"name":"Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA"},{"name":"Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0831-4189","authenticated-orcid":false,"given":"Ruben","family":"Prins","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA"},{"name":"Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8195-5703","authenticated-orcid":false,"given":"Sarah F.","family":"Hamm-Alvarez","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA"},{"name":"Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2321-3159","authenticated-orcid":false,"given":"W. Martin","family":"Kast","sequence":"additional","affiliation":[{"name":"Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA"},{"name":"Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kombe Kombe, A.J., Li, B., Zahid, A., Mengist, H.M., Bounda, G.-A., Zhou, Y., and Jin, T. (2021). Epidemiology and Burden of Human Papillomavirus and Related Diseases, Molecular Pathogenesis, and Vaccine Evaluation. Front. 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